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Biomedical subjects

M B Williams

Publications and source records attributed to M B Williams.

At least 19 recordsLinked to original sources
PubMed1995

Modulation by inositol of cholinergic- and serotonergic-induced seizures in lithium-treated rats.

Hippocampal and cortical EEG recordings in rats were used to monitor the in vivo modulation by lithium of responses to agonists for 5HT2/5HT1c serotonergic (DOI) and cholinergic (pilocarpine) receptors and the influence of inositol administration. Administration of DOI (8 mg/kg) or pilocarpine (30 mg/kg) to rats pretreated with lithium acutely (3 mmol/kg) or chronically (dietary, 4 weeks) resulted in seizures, whereas these doses did not cause seizures without lithium pretreatment. This indicated that lithium most likely affects a signal transduction process common to both systems, which is the phosphoinositide second messenger system. To examine the potential influence of altered inositol levels on these responses, we tested the effects of infusions (10 mg, i.c.v.) of myo-inositol, a precursor of phosphoinositide synthesis, and of epi-inositol, an isomer not used for phosphoinositide synthesis. Administration of myo-inositol (10 mg) slightly reduced the incidence of seizures induced by acute lithium plus DOI but almost completely blocked seizures induced by acute lithium plus pilocarpine. This was surprising since seizures induced by acute lithium plus DOI were less severe than those after acute lithium plus pilocarpine, but myo-inositol was more effective in blocking the latter. Epi-inositol also blocked seizures under both conditions but it was less effective than myo-inositol after treatment with acute lithium plus pilocarpine. The latencies to seizures and/or severity of seizures were potentiated more by chronic than acute lithium pretreatment with both DOI and pilocarpine, but attenuation by myo-inositol was less with each agonist after chronic lithium compared with acute lithium treatment. Peripheral administration of a high dose of myo-inositol blocked seizures induced by acute lithium plus pilocarpine, but the inositol treatment itself was toxic and caused seizures prior to pilocarpine administration, so the mechanism of action cannot simply be attributed to increased brain inositol levels. These results demonstrate that lithium modulates the in vivo responses to DOI and pilocarpine, most probably through an effect on the phosphoinositide signal transduction system. They also show that centrally administered myo-inositol modifies responses to these agents, but the effectiveness of epi-inositol and other results leave unclear the mechanistic basis of its actions.

Amphetamines↗
PubMed1995

Circadian variation in rat brain AP-1 DNA binding activity after cholinergic stimulation: modulation by lithium.

The potential influence of a circadian rhythm and its modulation by lithium on the stimulation of AP-1 DNA binding activity by the cholinergic agonist pilocarpine was investigated in rat cerebral cortex. Stimulation of AP-1 binding after pilocarpine (30 mg/kg) was evident within 1 h and was maximally stimulated by 200% at 2 h. Pilocarpine-stimulated AP-1 binding exhibited a circadian rhythm in AP-1 binding measured at 0800, 1200, and 1600 hours, 2 h after pilocarpine. Pilocarpine-stimulated AP-1 binding at 0800 hours was approximately twice the level measured at 1600 hours. After acute lithium treatment, pilocarpine administration induced generalized seizures after about 20 min and stimulated AP-1 binding which increased continuously for 4.5 h, at which time the stimulation was 900% above control. A circadian variation was apparent in AP-1 binding stimulated by acute lithium plus pilocarpine, with stimulation at 0800 hours being 1.5 times that at 1600 hours. After chronic lithium and pilocarpine, which also produced seizures, there was no circadian variation in pilocarpine-stimulated AP-1 binding. Thus pilocarpine-induced AP-1 binding in rat cerebral cortex was influenced by a circadian rhythm, but this was abolished by chronic lithium administration.

Animals↗
PubMed1994

Lithium potentiates phosphoinositide-linked 5-HT receptor stimulation in vivo.

The therapeutic effect of lithium in manic-depressive illness may involve alterations in the activity of the phosphoinositide second messenger system. Lithium administration to rats potentiates responses to cholinergic agonists, as evidenced by the production of seizures in lithium-treated rats after normally nonconvulsant doses of cholinergic agonists. We now report that lithium also potentiates the response to a serotonin (5-HT) agonist, DOI, that activates 5-HT2/5-HT1C receptors coupled to phosphoinositide hydrolysis. EEG recordings showed that administration of DOI (8 mg kg-1) to lithium-treated, but not to lithium-naive, rats caused seizures which were blocked by ritanserin pretreatment. These results demonstrate that lithium pretreatment causes a normally subconvulsive dose of serotonergic, in addition to cholinergic, agonists to induce seizures. Since DOI, like cholinergic agonists, activates receptors coupled with phosphoinositide hydrolysis and lithium potentiates responses to each, this second messenger system is likely to be involved in this effect of lithium.

Amphetamines↗
PubMed1994

Protein synthesis inhibitors attenuate seizures induced in rats by lithium plus pilocarpine.

The effects of two protein synthesis inhibitors, cycloheximide and anisomycin, were tested on seizures induced by coadministration of lithium and pilocarpine to rats. Systemic cycloheximide (2 mg/kg, s.c.) and centrally administered anisomycin (300 micrograms/10 microliters, i.c.v.) doubled the latency to initiation of seizures and to status epilepticus, while peripherally administered anisomycin (50 mg/kg, s.c.) completely blocked lithium-pilocarpine seizures. These results indicate that protein synthesis is required for initiation of seizures.

Animals↗
PubMed1994

Distinctive rat brain immediate early gene responses to seizures induced by lithium plus pilocarpine.

The mRNA levels of four immediate early genes (IEG) were measured in rat brain regions 60 min after administration of pilocarpine (30 mg/kg) to lithium-treated (3 mmol/kg) rats, during generalized convulsive status epilepticus. Northern blots demonstrated induction of the genes in the order of c-fos = jun-B > c-jun > jun-D with large increases in the cerebral cortex, hippocampus, and striatum, a smaller increase in the cerebellum, and less in the brainstem. The mRNA levels of these four IEG were measured in rat cerebral cortex and hippocampus at several times after administration of the cholinergic agonist pilocarpine (5 or 30 mg/kg) with or without lithium pretreatment (3 mmol/kg, 16 h prior, or chronic 4 week dietary administration). Treatment with pilocarpine (30 mg/kg) alone increased mRNA levels in the order of c-fos > jun-B > c-jun but did not change the jun-D mRNA level, and maximal c-fos and jun-B mRNA levels occurred earlier (30 min) in the cortex than in the hippocampus. Treatment with the lower dose of pilocarpine (5 mg/kg) alone caused only small increases in c-fos and jun-B mRNA levels and these responses were unaffected by lithium pretreatment. Lithium pretreatment potentiated IEG expression induced by 30 mg/kg pilocarpine, likely as a result of the seizures caused by this combination of drugs because pretreatment with anticonvulsants (diazepam or MK-801) blocked seizures and the enhanced IEG mRNA levels. The mRNA levels were increased during seizures in the order of c-fos > jun-B > c-jun > jun-D in the hippocampus and jun-B > c-fos > c-jun > jun-D in the cortex, and were increased for a longer duration as well as to a greater extent than after administration of pilocarpine alone. Administration of pilocarpine (30 mg/kg) to rats treated chronically with lithium caused increases similar to those measured with acute lithium pretreatment. Thus the induction of IEG by cholinergic stimulation varied with dose, time, and brain region, and unique responses were observed for each of the IEG. Lithium pretreatment did not impair IEG expression induced by the lower dose of pilocarpine and greatly enhanced expression of IEG after administration of the higher dose of pilocarpine concomitant with seizure activity.

Animals↗
PubMed1994

Prevention of gallium toxicity by hyperhydration in treatment of medulloblastoma.

In vitro and in vivo studies have established gallium nitrate as an effective chemotherapeutic agent against human medulloblastoma. In vitro, gallium nitrate reduced cell proliferation and DNA synthesis of medulloblastoma Daoy. Gallium inhibits the availability of 59Fe to ribonucleotide reductase and has a direct effect on the enzyme itself. In vivo, gallium demonstrated similar effects on the medulloblastoma Daoy cell line in nude mice. Tumor growth rate and actual size were decreased; however, severe nephrotoxicity and mortality were observed. In our study, intradermal injections of medulloblastoma Daoy cells were given to nude mice and then tumors were allowed to grow. Tumor-bearing mice received a 15-day gallium (50 mg/kg/day) regimen, 20-day rest, 7-day gallium (66.5 mg/kg/day) dose escalation regimen beginning when tumor size exceeded 8-10 mm in diameter. All treated and control mice received saline hyperhydration during both treatment sessions. Our study resulted in the prevention of severe toxicity and an inhibition of tumor growth. No toxicity occurred with gallium nitrate at 50 mg/kg/day. Severe morbidity and mortality were observed at the higher gallium dose level (66.5 mg/kg/day), suggesting that the 50 mg/kg/day dose is the appropriate level when investigating gallium nitrate as a chemotherapy agent in nude mice.

Animals↗
PubMed1994

Gallium nitrate delays the progression of microscopic disease in a human medulloblastoma murine model.

The goal of adjuvant chemotherapy is to treat postoperative microscopic disease in the hope of preventing tumor recurrence and/or metastasis. Since the introduction of chemotherapeutic agents, the disease-free survival of children with medulloblastoma has improved only modestly. Therefore, there is a need to develop and investigate new chemotherapeutic agents for this malignancy. Gallium nitrate has demonstrated significant antineoplastic activity toward human medulloblastoma in vitro and in vivo and may prove to be an optimal chemotherapeutic agent in treating medulloblastoma microscopic disease. The present study consisted of injecting medulloblastoma Daoy intradermally into both flanks of nude mice. A 15-day 50-mg/kg/day regimen was implemented the day after tumor inoculation. All treated and control mice received saline hyperhydration during the treatment period. The interval between tumor cell inoculation and first measurable tumor detection, tumor occurrence, growth rate, and size were recorded. Results indicated that gallium nitrate significantly prolonged the interval between tumor cell inoculation and measurable tumor detection.

Animals↗
PubMed1992

Modulation of endogenous ADP-ribosylation in rat brain.

Endogenous ADP-ribosylation of proteins was measured in homogenates, membranes, and cytosol from rat brain regions. Several proteins were ADP-ribosylated in homogenates, especially a 49 kDa protein. Sodium nitroprusside, a source of nitric oxide, particularly enhanced the ADP-ribosylation of 47 kDa and 39 kDa proteins. Levels of basal and sodium nitroprusside-stimulated ADP-ribosylated proteins were similar, but not identical, in homogenates from the cerebral cortex, hippocampus, striatum, thalamus and cerebellum. In neonatal cerebral cortex, ADP-ribosylation of an additional 110 kDa protein was detected and this was also enhanced by sodium nitroprusside. ADP-ribosylation of the 110 kDa protein was evident one and two days after birth, but not at five days and later. Each protein demonstrated unique sensitivities to sodium nitroprusside and rates of ADP-ribosylation. Cyclic GMP did not mimic the effects of sodium nitroprusside. Mg2+ inhibited ADP-ribosylation of the 49 kDa and 47 kDa proteins but had a smaller effect on the 39 kDa protein. ADP-ribosylation in the cytosol predominantly affected only a single protein of 39 kDa, and this was stimulated by sodium nitroprusside and by addition of cofactors necessary for activation of nitric oxide synthase. Several proteins in membranes were ADP-ribosylated and the 49 and 47 kDa proteins were released from the membranes coincidentally with ADP-ribosylation. The predominate substrates of endogenous ADP-ribosylation did not appear to be substrates for pertussis toxin-induced ADP-ribosylation. These and previously published results indicate that nitric oxide generated from sodium nitroprusside or endogenous sources may have modulatory effects through regulation of the endogenous ADP-ribosylation of proteins.

Adenosine Diphosphate Ribose↗
PubMed1990

Reduction of Na+ enhances phosphoinositide hydrolysis and differentiates the stimulatory and inhibitory responses to quisqualate in rat brain slices.

The concentration of Na+ in the incubation medium significantly influenced phosphoinositide hydrolysis induced by some, but not all, agonists in rat cerebral cortical slices. Reductions of the Na+ concentration below 120 mM resulted in incremental increases in basal and norepinephrine-stimulated accumulation of [3H]inositol monophosphate in cortical slices that had been prelabelled with [3H]inositol, and maximal responses were obtained with 0 and 5 mM Na+. In contrast, the responses to carbachol and ibotenate were similar in medium containing 120 or 5 mM Na+. In medium with 120 mM Na+, quisqualate has two effects on phosphoinositide hydrolysis in cortical slices, including a relatively weak stimulatory effect and an inhibitory modulation of the stimulation induced by norepinephrine. These two responses to quisqualate were differentially modulated by Na+; in 5 mM compared with 120 mM Na+ the stimulatory response was greatly increased and the inhibitory effect was mostly eliminated. That these were two separate events was confirmed by the use of L-BOAA (beta-N-oxalyl-L-alpha, beta-diaminopropionic acid), which reproduces the inhibitory, but not the stimulatory effect of quisqualate on phosphoinositide hydrolysis. In 5 mM Na+, inhibition by L-BOAA of norepinephrine-stimulated phosphoinositide hydrolysis was completely eliminated. These results demonstrate that a physiological concentration of Na+ maintains phosphoinositide hydrolysis at a submaximal level of sensitivity to some, but not all, agonists. The differential effects of Na+ on the stimulatory and inhibitory effects of quisqualate further substantiate the suggestion that these are two separate processes and indicate that alterations of the Na+ concentration may influence the effects of quisqualate, and other agonists, on phosphoinositide hydrolysis.

Animals↗
PubMed1989

Unilateral naris closure in adult mice: atrophy of the deprived-side olfactory bulbs.

The effects of unilateral naris closure, for 1-6 months, on the olfactory bulbs of adult mice were investigated in 3 experiments. The bulbs on the closed, or deprived, sides were smaller in a total of 68 out of 73 mice. Experiment 1 revealed a significant overall difference in cross-sectional areas of the open and closed-side bulbs of 6-, 8- or 12-week naris closure mice. In Expt. 2, in the 1-month naris closure group the difference in weights between the open and closed-side bulbs was a marginally significant 17% (P less than 0.06), while in the 3.5-month closure group the difference was 28% (P less than 0.01). In Expt. 3, after 6 months of naris closure the disparity was similarly 27% (P less than 0.01). A comparison of the size of control bulbs at the beginning of the 6-month closure period (Day 0 controls) with control sizes at the end of the period (6-month controls), revealed no significant difference (P greater than 0.05). This indicates that the smaller size of the closed-side bulbs is attributable to atrophy rather than arrested growth during the closure period. These data provide evidence that for olfaction, unlike other sensory systems, there may be no critical period during growth and development in which deprivation must occur in order to cause gross morphological changes in the CNS sensory structures. Thus the olfactory receptor neurons of adults appear to have a unique trophic relationship with their CNS target tissue, the olfactory bulbs.

Animals↗
PubMed1987

Sexual behavior and Down syndrome: the biological mechanism.

Sufficient evidence of a correlation between infrequent coitus and Down syndrome (DS) has now accumulated to warrant reevaluation of the suggested biological mechanisms. The evidence provides no support for delayed fertilization as the mechanism responsible for this correlation, as was originally proposed by German [Nature 217:516-519, 1968]. A better explanation of this association is provided by the sperm aging hypothesis, which gains its support from both animal studies and chromosomal findings of a paternal contribution to DS. The animal studies supporting this hypothesis show an increased incidence of sperm-derived trisomies resulting from sperm stored for prolonged periods in the male tract. The chromosomal findings show a paternal origin in 20% of DS infants; the sperm aging hypothesis concerns the biological mechanism in this 20%. In addition to explaining the excess of DS for older mothers, the sperm aging hypothesis explains the excess for teenage unwed mothers and indicates that sperm aging from decreased ejaculatory frequency may be a cause of DS in all age groups. Testable directly in humans against German's delayed fertilization hypothesis, the sperm aging hypothesis has immediate clinical implications. It suggests 1) an approach to reduce the incidence of DS and miscarriages and 2) clinical research that will increase knowledge of the circumstances indicating a need for antenatal monitoring.

Abortion, Spontaneous↗
PubMed1985

Calmodulin-dependent NAD kinase of human neutrophils.

NAD kinase from human neutrophils has been partially purified by sequential application of Red Agarose, ion-exchange, and gel-filtration chromatography. The enzyme has a broad pH optimum, 7.0-9.5, is strictly dependent upon the presence of Mg2+, and in the absence of calcium exhibits Km values of 0.6 and 0.9 mM for NAD and ATP, respectively. NAD kinase activity is extremely sensitive to free calcium concentration, with half-maximal activity observed at free calcium concentrations of approximately 0.4 microM. In cellular extracts calcium-dependent activation of NAD kinase increases the maximum velocity of the reaction from 2- to 5-fold while not affecting Km values for NAD and ATP. The activity of the partially purified NAD kinase is stimulated 3.5-fold by the addition of calmodulin in the presence of calcium. This stimulation is inhibited by the addition of 20 microM trifluoperazine to the incubation. These data are interpreted as implicating calmodulin in NAD kinase regulation. The total concentration of NADP + NADPH in the human neutrophil used increased 2.2-fold in response to activation by phorbol myristic acetate. Finally, neutrophil NAD kinase has a Mr, based upon gel filtration, of 169,000.

Adenosine Triphosphate↗